Aqueous liquid preparations and light-stabilized aqueous liquid preparations

ABSTRACT

An aqueous liquid preparation containing (+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric acid or a pharmacologically acceptable acid addition salt thereof, which is stabilized with a water-soluble metal chloride, is provided.

TECHNICAL FIELD

The present invention relates to an aqueous liquid preparationcomprising(+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric acidor a pharmacologically acceptable acid addition salt thereof, and awater-soluble metal chloride. The present invention also relates to amethod of light-stabilizing(+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric acidand a pharmacologically acceptable acid addition salt thereof, whichcomprises adding a water-soluble metal chloride.

BACKGROUND ART

(+)-(S)-4-[4-[(4-Chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric acidand a pharmacologically acceptable acid addition salt thereof have anantihistaminic action and an antiallergic action. They are alsocharacterized in that secondary effects such as stimulation orsuppression of the central nerve often seen in the case of conventionalantihistaminic agents can be minimized, and can be used as effectivepharmaceutical agents for the treatment of human and animals(JP-B-5-33953, JP-A-2000-198784).

Particularly, a tablet comprising(+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric acidmonobenzenesulfonate (general name: bepotastine besilate) has beenalready marketed as a therapeutic agent for allergic rhinitis anditching associated with hives and dermatoses.

On the other hand,(+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric acidand a pharmacologically acceptable acid addition salt thereof areunstable to light in an aqueous solution, and colored or predipitatedwith the lapse of time, which has made the use thereof as an aqueousliquid preparation difficult. In the case of an aqueous liquidpreparation such as an eye drop and a nasal drop, a method comprisingblocking light by preserving in a light-shielding container and the likecan be used, but complete light-shielding is practically difficult.Thus, stabilization of an aqueous liquid preparation itself as apreparation is desirable. As a method of light-stabilizing an eye drop,a U.S. Pat. No. 2,929,274 discloses a method comprising adding boricacid and/or borax and glycerin, but according to this method,stabilization of(+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric acidand a pharmacologically acceptable acid addition salt thereof to lightwas not observed. As a general stabilization method, a method comprisingplacing in the coexistence of an antioxidant such as BHT etc., and thelike are known (JP-A-7-304670).

DISCLOSURE OF THE INVENTION

The present invention aims at providing an aqueous liquid preparationcomprising stabilized(+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric acidor a pharmacologically acceptable acid addition salt thereof.

Another object of the present invention is to provide a method oflight-stabilizing(+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric acidand a pharmacologically acceptable acid addition salt thereof in anaqueous solution.

Under the above-mentioned situation, the present inventor has conductedvarious studies and, as a result, found that(+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric acidand a pharmacologically acceptable acid addition salt thereof can belight-stabilized in water by adding a water-soluble metal chloride, andfurther studied to complete the present invention.

Accordingly, the present invention relates to

-   (1) an aqueous liquid preparation comprising    (+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric    acid or a pharmacologically acceptable acid addition salt thereof,    and a water-soluble metal chloride,-   (2) the aqueous liquid preparation of the above-mentioned (1),    wherein the metal chloride has a concentration selected from the    range of a lower limit concentration of 0.15 w/v % and an upper    limit concentration of 1.5 w/v %,-   (3) the aqueous liquid preparation of the above-mentioned (1) or    (2), wherein the metal chloride is at least one kind selected from    sodium chloride, potassium chloride and calcium chloride,-   (4) the aqueous liquid preparation of any of the above-mentioned (1)    to (3), wherein the    (+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric    acid or the pharmacologically acceptable acid addition salt thereof    has a concentration selected from the range of a lower limit    concentration of 0.1 w/v % and an upper limit concentration of 2.0    w/v %,-   (5) the aqueous liquid preparation of any of the above-mentioned (1)    to (4), which is an acid addition salt of    (+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric    acid,-   (6) the aqueous liquid preparation of the above-mentioned (5),    wherein the acid addition salt is monobenzenesulfonate,-   (7) the aqueous liquid preparation of any of the above-mentioned (1)    to (6), wherein the aqueous liquid preparation has a pH in the range    of 4-8.5,-   (8) the aqueous liquid preparation of any of the above-mentioned (1)    to (7), which is an eye drop,-   (9) the aqueous liquid preparation of any of the above-mentioned (1)    to (7), which is a nasal drop,-   (10) an aqueous eye drop comprising    (+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric    acid monobenzenesulfonate and sodium chloride at not less than 0.2    w/v % and not more than 0.8 w/v %, and-   (11) a method of light-stabilizing    (+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric    acid in an aqueous solution, which comprises adding a water-soluble    metal chloride to an aqueous solution comprising    (+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric    acid or a pharmacologically acceptable acid addition salt thereof.

In the present invention, as a pharmacologically acceptable acidaddition salt of(+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butyricacid, for example, salts with hydrohalic acid such as hydrochloride,hydrobromide and the like; salts with inorganic acid such as sulfate,nitrate, phosphate and the like; salts with organic acid such asacetate, propionate, hydroxyacetate, 2-hydroxypropionate, pyruvate,malonate, succinate, maleate, fumarate, dihydroxyfumarate, oxalate,benzoate, cinnamate, salicylate, methanesulfonate, ethanesulfonate,benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate,4-aminosalicylate and the like; and the like can be mentioned. Theabove-mentioned compound to be used in the present invention isgenerally preferably an acid addition salt, and of these acid additionsalts, benzenesulfonate and benzoate are more preferable, andmonobenzenesulfonate is particularly preferable.

(+)-(S)-4-[4-[(4-Chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric acidand a pharmacologically acceptable acid addition salt thereof can beproduced by, for example, the methods described in JP-B-5-33953 andJP-A-2000-198784.

In the aqueous liquid preparation of the present invention, the contentof (+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butyricacid or a pharmacologically acceptable salt thereof asmonobenzenesulfonate is generally shown by a lower limit of about 0.1w/v %, preferably about 0.3 w/v %, more preferably about 0.5 w/v %, andan upper limit of about 2.0 w/v %, preferably about 1.5 w/v %, which areincreased or decreased appropriately depending on the object of use andthe degree of symptoms.

In the present invention, as a preferable water-soluble metal chloride,alkali metal chlorides such as sodium chloride, potassium chloride andthe like, and alkaline earth metal chlorides such as calcium chlorideand the like can be mentioned, which may be used alone, or incombination of two or more kinds thereof. Particularly preferred issodium chloride.

In the aqueous liquid preparation of the present invention, the contentof the water-soluble metal chloride is generally shown by a lower limitof about 0.15 w/v % and an upper limit of about 1.5 w/v %, preferably alower limit of about 0.2 w/v % and an upper limit of about 1.2 w/v %.Particularly, as sodium chloride, it is not less than about 0.15 w/v %,about 0.2 w/v %, about 0.3 w/v %, and not more than about 1.0 w/v %,about 0.8 w/v %, about 0.6 w/v %. As potassium chloride, it is not lessthan about 0.15 w/v %, about 0.2 w/v %, about 0.3 w/v %, and not morethan about 1.0 w/v %, about 0.9 w/v %, about 0.8 w/v %. As calciumchloride and as dihydrate, it is not less than about 0.2 w/v %, about0.3 w/v %, and not more than about 1.5 w/v %, about 1.2 w/v %.

Moreover, the concentration of these water-soluble metal chlorides ispreferably determined as appropriate within the above-mentionedconcentration range, such that the osmotic pressure is generally about230 mOsm-about 350 mOsm, in consideration of the amount of otherisotonic agents to be added, such as boric acid and the like, that donot influence stabilization.

Various additives that are generally used such as buffer, preservative,chelating agent, flavor and the like may be appropriately added to theaqueous liquid preparation of the present invention.

As the buffer, for example, phosphate buffer, borate buffer, citratebuffer, tartrate buffer, acetate buffer, amino acid and the like can bementioned. As the preservative, for example, quaternary ammonium saltssuch as benzalkonium chloride, chlorhexidine gluconate and the like,parahydroxybenzoic acid esters such as methyl parahydroxybenzoate,propyl parahydroxybenzoate and the like, sorbic acid and a salt thereofand the like can be mentioned. As the chelating agent, disodium edetate,citric acid and the like can be mentioned. As the flavor, 1-menthol,borneol, camphor, oil of eucalyptus and the like can be mentioned.

The pH of the aqueous liquid preparation of the present invention isadjusted to not less than about 4, 5, 6, and not more than about 8.5, 8.

In the aqueous liquid preparation of the present invention, other sameor different kinds of efficacious ingredients may be added appropriatelyas long as the object of the present invention is not impaired.

As the aqueous liquid preparation of the present invention, an eye drop,a nasal drop, an ear drop and the like can be mentioned. When theaqueous liquid preparation of the present invention is used as a nasaldrop, it may be prepared into a propellant.

The aqueous liquid preparation of the present invention can be producedby a production method known per se, such as a method described in theliquid preparation or eye drop of the General Rules for Preparations inthe Japanese Pharmacopoeia 14th Edition.

The aqueous liquid preparation of the present invention can be used forwarm-blooded animals (e.g., human, rat, mouse, rabbit, bovine, pig, dog,cat and the like).

When the aqueous liquid preparation of the present invention is used as,for example, an eye drop, it can be used for allergic conjunctivitis,spring catarrh, pollinosis and the like. The dose thereof when, forexample, an eye drop of the present invention comprising 1.0 w/v % of(+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric acidmonobenzenesulfonate (hereinafter to be referred to as bepotastinebesilate) is instilled into the eye of an adult, is 1-2 drops perinstillation, which is given 3-6 times a day by instillation into theeye. The frequency can be increased or decreased appropriately dependingon the degree of symptom.

BEST MODE FOR EMBODYING THE INVENTION

The present invention is explained in more detail by referring toExperimental Examples and Examples, which are not to be construed aslimitative.

EXPERIMENTAL EXAMPLE 1 Effect of Water-Soluble Metal Chloride onLight-Stability of Bepotastine Besilate Test Method

The aqueous liquid preparations (Formulations 1-6) shown in thefollowing [Table 1], which contained bepotastine besilate, were preparedaccording to conventional methods and filled in glass ampoules by 5 mLeach. Using a xenon long-life fade meter (FAL-25AX-Ec manufactured bySUGA TEST INSTRUMENTS Co., Ltd.), a light corresponding to not less than200 W·h/m² in a total near-ultraviolet radiation energy was irradiated(irradiation time: 23-34 hr), and appearance of each formulated liquidpreparation was observed. The amount of light exposure was measured by aquinine chemical actinometry system described in the Drug Approval andLicensing Procedures in Japan 2001.

TABLE 1 Formulation 1 2 3 4 5 6 bepotastine 1.5 g  1.5 g 1.5 g 1.5 g 1.5g  1.5 g  besilate sodium — 0.1 g 0.2 g 0.3 g — — chloride potassium — —— — 0.79 g  — chloride calcium — — — — — 1.18 g  chloride 2H₂O sodiumsuitable suitable suitable suitable suitable suitable hydroxide amountamount amount amount amount amount total 100 mL  100 mL  100 mL  100 mL100 mL 100 mL amount pH 7.0 7.0 6.7 6.9 6.7 6.8

Test Results

The appearance after light irradiation was black green in Formulation 1,and a precipitate was observed. It was slightly dark green—pale yellowin Formulation 2, and a precipitate was slightly observed. Formulations3-6 did not change from immediately after preparation and were paleyellow and clear. The results indicate that addition of a water-solublemetal chloride in not less than 0.2 w/v % improves stability ofbepotastine besilate under light irradiation conditions.

EXPERIMENTAL EXAMPLE 2 Effect of Boric Acid and Glycerin onLight-Stability of Bepotastine Besilate Test Method

The aqueous liquid preparations (Formulations 7-9) shown in thefollowing [Table 2], which contained bepotastine besilate, were preparedaccording to conventional methods and processed in the same manner as inExperimental Example 1, and appearance of each formulated liquidpreparation was observed.

TABLE 2 Formulation 7 8 9 bepotastine besilate 1.5 g 1.5 g 1.5 g sodiumdihydrogen 0.1 g — — phosphate dihydrate boric acid — 1.0 g 0.5 g sodiumchloride 0.6 g — — glycerin — 0.5 g 2.0 g benzalkonium chloride 0.005 g0.005 g 0.005 g sodium hydroxide suitable suitable suitable amountamount amount total amount 100 mL 100 mL 100 mL pH 6.8 6.8 6.8

Test Results

The appearance after light irradiation did not change from immediatelyafter preparation and was pale yellow and clear for Formulation 7comprising sodium chloride, but black green for Formulations 8 and 9comprising boric acid and glycerin and a precipitate was observed. Theresults indicate that addition of boric acid and glycerin fails toimprove stability of bepotastine besilate under light irradiationconditions.

EXPERIMENTAL EXAMPLE 3 Effect of pH and Bepotastine BesilateConcentration on Light-Stability of Bepotastine Besilate Test Method

The aqueous liquid preparations (Formulations 10-12) shown in thefollowing [Table 3], which contained bepotastine besilate, were preparedaccording to conventional methods and processed in the same manner as inExperimental Example 1, and appearance of each formulated liquidpreparation was observed.

TABLE 3 Formulation 10 11 12 bepotastine besilate 1.5 g 1.5 g 0.1 gsodium dihydrogen 0.1 g 0.1 g 0.1 g phosphate dihydrate sodium chloride0.6 g 0.6 g 0.82 g benzalkonium 0.005 g 0.005 g 0.005 g chloride sodiumhydroxide suitable suitable suitable amount amount amount total amount100 mL 100 mL 100 mL pH 4.0 8.5 6.8

Test Results

The appearance after light irradiation did not change from immediatelyafter preparation and was pale yellow and clear for Formulation 10 (pH4) and Formulation 11 (pH 8.5) comprising sodium chloride. In addition,the appearance did not change from immediately after preparation and wascolorless and clear for Formulation 12 having a bepotastine besilateconcentration of 0.1 w/v %. These results and the results of Formulation7 (pH 6.8) in Experimental Example 2 indicate that addition of sodiumchloride, which is a water-soluble metal chloride, improves lightstability of bepotastine besilate at pH 4-8.5. In addition, theyindicate that the light-stability of bepotastine besilate is improved inthe concentration range of 0.1 w/v %-1.5 w/v %.

EXPERIMENTAL EXAMPLE 4 Effect of Bepotastine Besilate Concentration andpH on Light-Stability of Bepotastine Besilate in Aqueous PreparationComprising Glycerin Test Method

The aqueous liquid preparations (Formulations 13-17) shown in thefollowing [Table 4], which contained bepotastine besilate, were preparedaccording to conventional methods and processed in the same manner as inExperimental Example 1, and appearance of each formulated liquidpreparation was observed.

TABLE 4 Formulation 13 14 15 16 17 bepotastine 0.5 g 1.0 g 1.5 g 1.5 g1.5 g besilate sodium 0.1 g 0.1 g 0.1 g 0.1 g 0.1 g dihydrogen phosphatedihydrate glycerin 2.2 g 2.0 g 1.7 g 1.7 g 1.7 g ben- 0.005 g 0.005 g0.005 g 0.005 g 0.005 g zalkonium chloride sodium suitable suitablesuitable suitable suitable hydroxide amount amount amount amount amounttotal amount 100 mL 100 mL 100 mL 100 mL 100 mL pH 6.8 6.8 4.0 6.8 8.5

Test Results

The appearance after light irradiation was pale black green forFormulation 13 and black green for Formulation 14, and a precipitate wasobserved in both Formulations. The results indicate that addition ofglycerin results in coloration of bepotastine besilate into black greeneven at a low concentration.

Formulation 15 (pH 4) turned blue and a precipitate was observed.Formulation 16 (pH 6.8) turned black green and a precipitate wasobserved. Formulation 17 (pH 8.5) turned yellow brown but noprecipitation was observed. The results indicate that bepotastinebesilate is extremely unstable at a pH near neutral. The results alsoindicate that glycerin does not improve light-stability of bepotastinebesilate in the range of pH 4-8.5. When 3.3 w/v % of glucose or mannitolwas added instead of glycerin of Formulation 16, black green wasdeveloped and a precipitate was observed. These results indicate that awater-soluble metal chloride improves light-stability of bepotastinebesilate, and isotonic agents such as glycerin, saccharides and the likedo not improve light-stability of bepotastine besilate.

EXAMPLE 1 Eye Drop

bepotastine besilate 0.3 g Sodium dihydrogenphosphate dihydrate 0.1 gsodium chloride 0.79 g  benzalkonium chloride 0.005 g  sodium hydroxidesuitable amount sterile purified water total amount 100 mL pH 6.8

Using the above-mentioned ingredients, an eye drop is prepared by aconventional method.

EXAMPLE 2 Eye Drop

bepotastine besilate 0.5 g Sodium dihydrogenphosphate dihydrate 0.1 gsodium chloride 0.76 g  benzalkonium chloride 0.005 g  sodium hydroxidesuitable amount sterile purified water total amount 100 mL pH 6.8

Using the above-mentioned ingredients, an eye drop is prepared by aconventional method.

EXAMPLE 3 Eye Drop

bepotastine besilate 1.0 g Sodium dihydrogenphosphate dihydrate 0.1 gsodium chloride 0.68 g  benzalkonium chloride 0.005 g  sodium hydroxidesuitable amount sterile purified water total amount 100 mL pH 6.8

Using the above-mentioned ingredients, an eye drop is prepared by aconventional method.

EXAMPLE 4 Eye Drop

bepotastine besilate 1.5 g Sodium acetate trihydrate 0.1 g sodiumchloride 0.6 g benzalkonium chloride 0.005 g  sodium hydroxide suitableamount sterile purified water total amount 100 mL pH 4.0

Using the above-mentioned ingredients, an eye drop is prepared by aconventional method.

EXAMPLE 5 Eye Drop

bepotastine besilate 1.5 g epsilon-aminocaproic acid 0.1 g sodiumchloride 0.6 g benzalkonium chloride 0.005 g  sodium hydroxide suitableamount sterile purified water total amount 100 mL pH 4.0

Using the above-mentioned ingredients, an eye drop is prepared by aconventional method.

EXAMPLE 6 Eye Drop

bepotastine besilate 1.5 g citric acid 0.1 g sodium chloride 0.6 gbenzalkonium chloride 0.005 g  sodium hydroxide suitable amount sterilepurified water total amount 100 mL pH 6.8

Using the above-mentioned ingredients, an eye drop is prepared by aconventional method.

EXAMPLE 7 Eye Drop

bepotastine besilate 1.5 g taurine 0.1 g sodium chloride 0.6 gbenzalkonium chloride 0.005 g  sodium hydroxide suitable amount sterilepurified water total amount 100 mL pH 8.5

Using the above-mentioned ingredients, an eye drop is prepared by aconventional method.

EXAMPLE 8 Eye Drop

bepotastine besilate 1.5 g sodium dihydrogenphosphate dihydrate 0.1 gsodium chloride 0.6 g methyl parahydroxybenzoate 0.026 g  propylparahydroxybenzoate 0.014 g  sodium hydroxide suitable amount sterilepurified water total amount 100 mL pH 6.8

Using the above-mentioned ingredients, an eye drop is prepared by aconventional method.

EXAMPLE 9 Eye Drop

bepotastine besilate 1.5 g sodium dihydrogenphosphate dihydrate 0.1 gsodium chloride 0.6 g potassium sorbate 0.27 g  sodium hydroxidesuitable amount sterile purified water total amount 100 mL pH 6.8

Using the above-mentioned ingredients, an eye drop is prepared by aconventional method.

EXAMPLE 10 Eye Drop

bepotastine besilate 1.5 g sodium dihydrogenphosphate dihydrate 0.1 gsodium chloride 0.6 g chlorhexidine gluconate 0.005 g  sodium hydroxidesuitable amount sterile purified water total amount 100 mL pH 6.8

Using the above-mentioned ingredients, an eye drop is prepared by aconventional method.

EXAMPLE 11 Eye Drop

bepotastine besilate 1.5 g sodium dihydrogenphosphate dihydrate 0.1 gsodium chloride 0.6 g benzalkonium chloride 0.005 g  sodium hydroxidesuitable amount sterile purified water total amount 100 mL pH 6.8

Using the above-mentioned ingredients, an eye drop is prepared by aconventional method.

EXAMPLE 12 Nasal Drop

bepotastine besilate 1.0 g sodium dihydrogenphosphate dihydrate 0.1 gsodium chloride 0.68 g  benzalkonium chloride 0.005 g  sodium hydroxidesuitable amount sterile purified water total amount 100 mL pH 6.8

Using the above-mentioned ingredients, a nasal drop is prepared by aconventional method.

INDUSTRIAL APPLICABILITY

In the present invention, the light-stability of(+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric acidor a pharmacologically acceptable acid addition salt thereof,particularly bepotastine besilate, which is monobenzenesulfonate, can beimproved by adding a water-soluble metal chloride to an aqueous liquidpreparation comprising(+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric acidor a pharmacologically acceptable acid addition salt thereof, and astable aqueous liquid preparation can be produced. Since an aqueousliquid preparation stable to light can be obtained by thelight-stabilizing method of the present invention, the aqueous liquidpreparation of the present invention is advantageously used for thetreatment of allergic conjunctivitis, spring catarrh, pollinosis,allergic rhinitis and the like.

While some of the embodiments of this invention have been described indetail in the foregoing, it will be possible for those of ordinary skillin the art to variously modify and change the embodiments specificallyshown herein, within the scope not substantially deviating from thenovel teaching and benefit of the invention. Accordingly, this inventionencompasses all such modifications and changes within the spirit andscope of the invention as defined by the following claims.

This application is based on a patent application No. 223804/2002 filedin Japan, the contents of which are hereby incorporated by reference.

1-11. (canceled)
 12. An aqueous liquid preparation consisting of, in anaqueous solution: (a) an active ingredient consisting of(+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric acidor a pharmacologically acceptable acid addition salt thereof; (b) awater-soluble metal chloride in a light-stabilizing effective amount;(c) water; and (d) at least one material selected from the groupconsisting of a buffer, a preservative, a chelating agent, sodiumhydroxide, and a flavor; wherein the(+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric acidor the pharmacologically acceptable acid addition salt thereof has aconcentration selected from the range of a lower limit concentration of0.1 w/v % and an upper limit concentration of 2.0 w/v %; and wherein themetal chloride has a concentration selected from the range of a lowerlimit concentration of 0.15 w/v % and an upper limit concentration of1.5 w/v %.
 13. The aqueous liquid preparation according to claim 12,wherein the metal chloride is selected from the group consisting ofsodium chloride, potassium chloride and calcium chloride.
 14. Theaqueous liquid preparation according to claim 12, wherein the acidaddition salt is monobenzenesulfonate.
 15. The aqueous liquidpreparation according to claim 12, wherein the aqueous liquidpreparation has a pH in the range of 4-8.5.
 16. The aqueous liquidpreparation according to claim 12, wherein the metal chloride has aconcentration selected from the range of a lower limit concentration of0.2 w/v % and an upper limit concentration of 1.2 w/v %.
 17. The aqueousliquid preparation according to claim 12, wherein the metal chloride hasa concentration selected from the range of a lower limit concentrationof 0.3 w/v % and an upper limit concentration of 1.2 w/v %.
 18. Theaqueous liquid preparation according to claim 12, wherein the metalchloride is sodium chloride and has a concentration selected from therange of a lower limit concentration of 0.3 w/v % and an upper limitconcentration of 1.0 w/v %.
 19. The aqueous liquid preparation accordingto claim 12, wherein the(+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric acidor the pharmacologically acceptable acid addition salt thereof has aconcentration selected from the range of a lower limit concentration of0.3 w/v % and an upper limit concentration of 2.0 w/v %.
 20. The aqueousliquid preparation according to claim 12, wherein the(+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric acidor the pharmacologically acceptable acid addition salt thereof has aconcentration selected from the range of a lower limit concentration of0.3 w/v % and an upper limit concentration of 1.5 w/v %.
 21. The aqueousliquid preparation according to claim 12, wherein the(+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric acidor the pharmacologically acceptable acid addition salt thereof has aconcentration selected from the range of a lower limit concentration of0.5 w/v % and an upper limit concentration of 1.5 w/v %.
 22. The aqueousliquid preparation according to claim 12, which is an eye drop.
 23. Theaqueous liquid preparation according to claim 12, which is a nasal drop.24. The aqueous liquid preparation according to claim 12, wherein: (a)the acid addition salt of the(+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric acidis monobenzenesulfonate salt, and the acid addition salt has aconcentration selected from the range of a lower limit concentration of0.3 w/v % and an upper limit concentration of 1.5 w/v %; (b) thewater-soluble metal chloride is selected from the group consisting ofsodium chloride, potassium chloride, and calcium chloride, and the metalchloride has a concentration selected from the range of a lower limitconcentration of 0.3 w/v % and an upper limit concentration of 1.0 w/v%; and the aqueous liquid preparation has a pH min the range of 5-8. 25.The aqueous liquid preparation according to claim 24, wherein the metalchloride is sodium chloride.
 26. The aqueous liquid preparationaccording to claim 24, wherein the metal chloride is potassium chloride.27. An aqueous eye drop consisting of: (a) an active ingredientconsisting of(+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric acidor a pharmacologically acceptable acid addition salt thereof; (b) atleast one water-soluble metal chloride selected from the groupconsisting of sodium chloride, potassium chloride, and calcium chloride;(c) sodium dihydrogenphosphate buffer; (d) a preservative; (e) water;and (f) sodium hydroxide; wherein the metal chloride has a concentrationselected from the range of a lower limit concentration of 0.2 w/v % andan upper limit concentration of 1.2 w/v %; and wherein the pH is in therange of 5-8.
 28. The aqueous liquid preparation according to claim 27,wherein the acid addition salt is monobenzenesulfonate.
 29. The aqueousliquid preparation according to claim 27, wherein the metal chloride hasa concentration selected from the range of a lower limit concentrationof 0.3 w/v % and an upper limit concentration of 1.2 w/v %.
 30. Theaqueous liquid preparation according to claim 27, wherein the metalchloride is sodium chloride and has a concentration selected from therange of a lower limit concentration of 0.3 w/v % and an upper limitconcentration of 1.0 w/v %.
 31. The aqueous liquid preparation accordingto claim 27, wherein the(+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric acidor the pharmacologically acceptable acid addition salt thereof has aconcentration selected from the range of a lower limit concentration of0.3 w/v % and an upper limit concentration of 2.0 w/v %.
 32. The aqueousliquid preparation according to claim 27, wherein the(+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric acidor the pharmacologically acceptable acid addition salt thereof has aconcentration selected from the range of a lower limit concentration of0.3 w/v % and an upper limit concentration of 1.5 w/v %.
 33. The aqueousliquid preparation according to claim 27, wherein the(+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric acidor the pharmacologically acceptable acid addition salt thereof has aconcentration selected from the range of a lower limit concentration of0.5 w/v % and an upper limit concentration of 1.5 w/v %.
 34. An aqueousliquid preparation consisting of, in an aqueous solution: (a) an activeingredient consisting of(+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric acidor a pharmacologically acceptable acid addition salt thereof; (b) awater-soluble metal chloride; (c) benzalkonium chloride; (d) sodiumdihydrogenphosphate dihydrate; (e) sodium hydroxide; and (f) water;wherein the metal chloride is sodium chloride and has a concentrationselected from the range of a lower limit concentration of 0.3 w/v % andan upper limit concentration of 1.0 w/v %; and wherein the pH is in therange of 6-8.
 35. The aqueous liquid preparation according to claim 34,wherein the active ingredient consists of(+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric acidmonobenzenesulfonate.
 36. The aqueous liquid preparation according toclaim 35, wherein the sodium chloride has a concentration selected fromthe range of a lower limit concentration of 0.3 w/v % and an upper limitconcentration of 0.8 w/v %.
 37. The aqueous liquid preparation accordingto claim 36, wherein the active ingredient has a concentration selectedfrom the range of a lower limit concentration of 0.3 w/v % and an upperlimit concentration of 2.0 w/v %.
 38. The aqueous liquid preparationaccording to claim 37, wherein the active ingredient has a concentrationselected from the range of a lower limit concentration of 0.3 w/v % andan upper limit concentration of 1.5 w/v %.
 39. The aqueous liquidpreparation according to claim 37, wherein the active ingredient has aconcentration selected from the range of a lower limit concentration of0.5 w/v % and an upper limit concentration of 1.5 w/v %.
 40. The aqueousliquid preparation according to claim 34, wherein (a) the acid additionsalt of the(+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric acidis monobenzenesulfonate salt, and the monobenzenesulfonate salt has aconcentration selected from the range of a lower limit concentration of0.5 w/v % and an upper limit concentration of 1.5 w/v %; and (b) thewater-soluble metal chloride is sodium chloride, and the sodium chloridehas a concentration selected from the range of a lower limitconcentration of 0.3 w/v % and an upper limit concentration of 0.8 w/v%.
 41. The aqueous liquid preparation according to claim 40, wherein themonobenzenesulfonate salt has a concentration of 1.5 w/v %.